Despite ongoing research into the treatment of cocaine abuse, effective medications for this substance related disorder (SRD) are still lacking. The National Survey on Drug Use and Health reported that rates of cocaine use have remained high, and the annual number of new users was unchanged from 2006-2007. This domestic user demand is easily met by Mexican DTOs and criminal groups, which now control most wholesale cocaine distribution in the U.S. Of recent concern, the violence and corruption associated with drug trafficking activities of Mexican cartels has greatly escalated in both Mexico and along the U.S.-Mexico border. In addition to the medical relevance of treating this SRD, the development of better therapies for addiction is crucial as a means to curtail U.S. demand for cocaine from increasingly powerful drug cartels. A major goal of currently funded research (R01 DA08590) is the design of human anti-cocaine monoclonal antibodies (mAbs). A recent focus has included the optimization of immunopharmacotherapeutic strategies for individual cocaine abuse scenarios so as to better address the human condition. Our research suggests that scenarios involving overdose or acute cocaine binges are best counteracted by the administration of smaller mAb fragments with rapid clearance rates;these observations were previously undocumented. Along this vein, the first specific aim of this research strategy will consist of: (1a-c) an examination of the pharmacokinetic properties and preclinical therapeutic efficacy of a candidate human anti- cocaine mAb and an engineered manifold in rodent models of severe cocaine toxicity. This will entail a rigorous analysis into the correlation between mAb fragment half-life and overdose rescue with the human anti-cocaine mAb GNCgzk, which possesses the highest affinity for cocaine (Kd,app= 3.4 nM) of fully human anti-cocaine mAbs reported in the literature. In response to the lack of a clinically effective active immunization strategy to treat cocaine addiction, the second specific aim strives to challenge the current dogma of cocaine vaccine design through (2a) probing a link between hapten stability and reactivity under active vaccination protocols, (2b) reformulating vaccine components to incorporate self-adjuvating carriers, and (2c) evaluating vaccine immunogenicity via cocaine self-administration assays in rats. The hypothesized results of specific aim 2 will address the scenario of hazardous cocaine binges because better active vaccines are required to elicit a more robust antibody response and thereby counteract excessive cocaine intake. The proposed optimization of anti- cocaine passive and active vaccines bypasses the barriers faced by other immunopharmacotherapeutics. Specifically, the poor catalytic efficiency of cocaine-degrading mAbs, the uncertain druggability of cocaine esterases, and the weak immunogenicity of current active vaccines, which represent the only anti-cocaine therapy tested in humans, have established cocaine-binding mAbs and, upon further refinement, anti-cocaine vaccines as the only clinically viable immunopharmacotherapeutic treatments for cocaine abuse. PUBLIC HEALTH RELEVANCE: By further refining human cocaine-binding monoclonal antibodies and candidate active vaccines, our initiatives will ultimately bring therapeutic agents closer to treating human cocaine addiction, a substance related disorder (SRD) that continues to pose a substantial medical and societal threat. The two aims investigate high-impact projects within passive and active immunization strategies, respectively, and share the goal of optimizing the anti-cocaine effect of the immunotherapeutic agent.